ID
45224
Description
Principal Investigator: Mary V. Relling, PharmD, St. Jude Children's Research Hospital, Memphis, TN USA MeSH: Acute Lymphoblastic Leukemia https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000426 Methotrexate plasma concentration is related to its clinical effects. To identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL), we performed a genome-wide analysis (GWAS) of 500,568 germline single-nucleotide polymorphisms (SNPs) in 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients. Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, *SLCO1B1* (rs11045879 (P = 1.7 x 10sup-10/sup) and rs4149081 (P = 1.7 x 10sup-9/sup) (Trevino et al, PMID: 19901119). To test whether rare variants in *SLCO1B1* could alter its function, we genotyped *SLCO1B1* exons in a slightly larger group of 699 children with ALL who received methotrexate and identified 93 single nucleotide polymorphisms (SNPs). We found several common and rare non-synonymous (NS) SNPs associated with methotrexate clearance. NS SNPs predicted to be functionally damaging (common or rare) were more likely to be found among patients with the lowest adjusted methotrexate clearance (lowest 10%) than patients with high clearance (highest 10%). Four *SLCO1B1* haplotypes were associated with reduced methotrexate clearance and we verified that these haplotypes have lower function with in vitro transport assays. We were able to quantitatively account for a third of the population variability in clearance of methotrexate with clinical and genetic covariates. This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays, sequencing, and genotyping.
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Versions (2)
- 29/07/2022 29/07/2022 - Simon Heim
- 12/10/2022 12/10/2022 - Adrian Schulz
Détendeur de droits
Mary V. Relling, PharmD, St. Jude Children's Research Hospital, Memphis, TN USA
Téléchargé le
12 octobre 2022
DOI
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Licence
Creative Commons BY 4.0
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dbGaP phs000426 SLCO1B1 Variants and Methotrexate Clearance
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- Subject ID and consent group of children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
- Sample ID and subject ID of children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
- Subject ID, methotrexate clearance over multiple courses, and methotrexate clearance adjustment obtained from children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
- Sample ID, tumor status, body site where from samples were collected, time point of treatment when samples were collected, and sample type obtained from children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
Similar models
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- Subject ID and consent group of children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
- Sample ID and subject ID of children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
- Subject ID, methotrexate clearance over multiple courses, and methotrexate clearance adjustment obtained from children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
- Sample ID, tumor status, body site where from samples were collected, time point of treatment when samples were collected, and sample type obtained from children with newly diagnosed acute lymphoblastic leukemia and involved in the "SLCO1B1 Variants and Methotrexate Clearance" project.
C0023492 (UMLS CUI [1,2])
C0023449 (UMLS CUI [1,3])
C0001779 (UMLS CUI [1,2])
C0021430 (UMLS CUI [1,2])
C0087111 (UMLS CUI [1,2])
C0444956 (UMLS CUI [1,3])
C0025677 (UMLS CUI [1,4])